Method of purifying 1,3,5-triisopropylbenzene

ABSTRACT

The present invention relates to a method of purifying 1,3,5-triisopropylbenzene that comprises combining impure 1,3,5-triisopropylbenzene with a sulfonating agent to form a reaction mixture, mixing the reaction mixture at a temperature at about 20° C. or above, and collecting the purified 1,3,5-triisopropylbenzene.

FIELD OF THE INVENTION

[0001] This invention relates to a method of purifying1,3,5-triisopropylbenzene.

BACKGROUND OF THE INVENTION

[0002] 1,3,5-Triisopropylbenzene is a known compound that can becommercially purchased. 1,3,5-Triisopropylbenzene is used in thesynthesis of 2,6-bis(1-methylethyl)phenyl[[2,4,6-tris(1-methylethyl)phenyl]-acetyl]sulfamate, which can beused as a lipid regulator. Because 2,6-bis(1-methylethyl)-phenyl[[2,4,6-tris(1-methylethyl)phenyl]acetyl]-sulfamate is a pharmaceuticalintended for human use, its purity must be high. Therefore, insynthesizing 2,6-bis(1-methylethyl)phenyl[[2,4,6-tris(1-methylethyl)phenyl]acetyl]sulfamate, the purity of starting materials andintermediates in the synthesis is important. Thus, it is desirable toobtain 1,3,5-triisopropylbenzene having a high purity.

[0003] It is difficult to obtain 1,3,5-triisopropylbenzene having apurity of greater than 98% of 1,3,5-triisopropylbenzene. For example,1,3,5-triisopropylbenzene can be purified to greater than 98% by vacuumdistillation, but the distillation apparatus must contain over 120theoretical plates, which is expensive and time consuming. Moreover,commercially available 1,3,5-triisopropylbenzene typically is not aspure as desired and must be further purified. For example,1,3,5-triisopropylbenzene having a purity of only 97.6% can be purchasedfrom Aldrich, Milwaukee, Wis.

[0004] The present invention provides a simple and efficient method forpurifying 1,3,5-triisopropylbenzene to purities greater than 97.6% of1,3,5-triisopropylbenzene.

SUMMARY OF THE INVENTION

[0005] The present invention provides a method of purifying1,3,5-triisopropylbenzene that comprises combining impure1,3,5-triisopropylbenzene with a sulfonating agent to form a reactionmixture, mixing the reaction mixture at a temperature of about 0° C. orabove; and collecting the purified 1,3,5-triisopropylbenzene.

[0006] In a preferred embodiment of the method, the sulfonating agentcomprises chlorosulfonic acid.

[0007] In another preferred embodiment, the sulfonating agent is about20 mol percent of the impure 1,3,5-triisopropylbenzene.

[0008] In another preferred embodiment, the sulfonating agent is in therange of about 15 mol percent to about 30 mol percent of the impure1,3,5-triisopropylbenzene.

[0009] In another preferred embodiment, the reaction mixture is mixed ata temperature in the range of about 0° C. to about 50° C.

[0010] In another preferred embodiment, the reaction mixture is mixed ata temperature in the range of about 20° C. to about 30° C.

[0011] In another preferred embodiment, the reaction mixture is mixed atroom temperature.

[0012] In another preferred embodiment, the sulfonating agent comprisesfluorosulfonic acid or sulfuric acid.

[0013] In another preferred embodiment, the reaction mixture is mixedfor at least 5 minutes.

[0014] In another preferred embodiment, the reaction mixture is mixedfor about 5 minutes to about 24 hours.

[0015] In another preferred embodiment, the reaction mixture is mixedfor about 5 minutes to about 60 minutes.

[0016] In another preferred embodiment, the purified1,3,5-triisopropylbenzene is collected by extracting the reactionmixture first with water, second with a base or an aqueous alcoholicsolution, and last with water.

[0017] In another preferred embodiment, the purified1,3,5-triisopropylbenzene is collected by extracting the reactionmixture with a base or an aqueous alcoholic solution.

[0018] In another preferred embodiment, the base is sodium hydroxide.

[0019] In another preferred embodiment, the sodium hydroxide has aconcentration of about 5 percent to about 50 percent by weight sodiumhydroxide to water.

[0020] In another preferred embodiment, the sodium hydroxide has aconcentration of about 5 percent to about 20 percent by weight sodiumhydroxide to water.

[0021] In another preferred embodiment, the sodium hydroxide has aconcentration of about 5 percent by weight sodium hydroxide to water.

[0022] In another preferred embodiment, the base comprises sodiumbicarbonate, ammonia or sodium hydroxide, or mixtures thereof.

[0023] In another preferred embodiment, the aqueous alcoholic solutionis a methanol and water solution.

[0024] In a more preferred embodiment, the methanol and water solutionis a 50 percent by volume methanol to water solution.

[0025] In another preferred embodiment, the base is 5 percent by weightsodium bicarbonate to water, or 30 percent by weight ammonia to water.

[0026] In a most preferred embodiment, the present invention provides amethod of purifying 1,3,5-triisopropylbenzene that comprises combiningimpure 1,3,5-triisopropylbenzene with about 20 mole percentchlorosulfonic acid to the 1,3,5-triisopropylbenzene to form a reactionmixture, mixing the reaction mixture at a temperature in the range ofabout 0° C. to about 50° C. for a time in the range of about 10 minutesto about 24 hours, and collecting the purified 1,3,5-triisopropylbenzeneby first extracting the reaction mixture with water, next extracting thereaction mixture with sodium hydroxide having a concentration in therange of about 5 percent to about 50 percent by weight sodium hydroxideto water, and last extracting the reaction mixture with water.

DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention provides a method of purifying1,3,5-triisopropylbenzene that comprises combining impure1,3,5-triisopropylbenzene with a sulfonating agent to form a reactionmixture, mixing the reaction mixture at a temperature at about 0° C. orabove, and collecting the purified 1,3,5-triisopropylbenzene.

[0028] In general, impure 1,3,5-triisopropylbenzene is combined with asulfonating agent in a suitable container such as a round-bottomed flaskto form a reaction mixture, and the mixture is mixed by stirring orshaking or the like.

[0029] The term “impure 1,3,5-triisopropylbenzene” means1,3,5-triisopropylbenzene that contains impurities that are desired tobe removed. For example, 1,3,5-triisopropylbenzene that has a purity of97.6% with respect to 1,3,5-triisopropylbenzene can be purchased fromAldrich, Milwaukee, Wis. However, it is desirable to have a purity of98%. Preferably, the purity of the 1,3,5-triisopropylbenzene is greaterthan 98% and most preferably greater than 99%. The purities expressedherein are area percents obtained by vapor phase chromatography as setforth below.

[0030] The sulfonating agent can be selected from those sulfonatingagents known to those skilled in the art. The sulfonating agent ispreferably inexpensive and should provide for greater sulfonation of theimpurities than of 1,3,5-triisopropylbenzene. In general, the majorimpurities seen in impure 1,3,5-triisopropylbenzene include1,2,4-triisopropylbenzene and ethyldiisopropylbenzenes. Examples ofsuitable sulfonating agents include, but are not limited to,chlorosulfonic acid, fluorosulfonic acid, sulfur trioxide and sulfuricacid. Preferably, the sulfonating agent is chlorosulfonic acid.

[0031] The sulfonating agent is combined with impure1,3,5-triisopropylbenzene in an amount that is in the range of about 15mol to about 50 mole percent sulfonating agent to1,3,5-triisopropylbenzene. Preferably, the sulfonating agent is used inan amount that is in the range of about 15 mol to about 30 mol percentsulfonating agent to 1,3,5-triisopropylbenzene. In a preferredembodiment, the sulfonating agent is chlorosulfonic acid, and the amountof the chlorosulfonic is 20 mol percent with respect to the1,3,5-triisopropylbenzene.

[0032] The mixture of 1,3,5-triisopropylbenzene and the sulfonatingagent are mixed by methods that are well-known to those skilled in theart at a temperature in the range of about 0° C. or above. Preferably,the temperature of the reaction mixture is in the range of about 0° C.to about 50° C. More preferably, the temperature of the reaction mixtureis in the range of about 20° C. to 30° C. Most preferably, thetemperature of the reaction mixture is about room temperature. Ingeneral, room temperature is about 23° C. However, room temperature canvary a few degrees. For example, room temperature can include thetemperatures in the range of about 25° C. to about 20° C.

[0033] The reaction mixture is mixed at the desired temperature for atleast 5 minutes. Preferably, the reaction mixture is mixed at thedesired temperature in the range of about 5 minutes to about 24 hours.More preferably, the reaction mixture is mixed at the desiredtemperature in the range of about 5 minutes to about 60 minutes. It isnoted that the reaction time necessary to obtain the desired purity of1,3,5-triisopropylbenzene can vary depending on the temperature of thereaction mixture.

[0034] After the reaction mixture is mixed for the desired time andtemperature, the purified 1,3,5-triisopropylbenzene is collected. Thepurified 1,3,5-triisopropylbenzene can be collected by a series ofextractions or by a single extraction. For example, the purified1,3,5-triisopropylbenzene can be collected by extracting the reactionmixture with water, then extracting the reaction mixture with a base oran aqueous alcoholic solution, and then extracting the reaction mixturewith water. In general, the sulfonated impurities can be removed byextraction into an aqueous solution or by conversion of the sulfonatedimpurities into a salt using a base and then extracting into an aqueoussolution. Typically, the volume of the extracting liquid is equal to orgreater than the volume of the reaction mixture. Preferably, the volumeof the extracting liquid is in the range of about one to about 10 timesthe volume of the reaction mixture.

[0035] Alternatively, the purified 1,3,5-triisopropylbenzene can becollected by extracting with a base using a single extraction or aseries of basic extractions. In another purification method, thepurified 1,3,5-triisopropylbenzene can be collected by extracting with abase using a single extraction or a series of basic extractions followedby a single or a series of extractions with water.

[0036] An aqueous alcoholic solution is a mixture that contains analcohol and water. Examples of suitable alcohols include methanol,ethanol, propanol, isopropanol and the like.

[0037] Suitable bases are well-known to those skilled in the art.Examples of suitable bases include, but are not limited to, sodiumhydroxide, ammonia, sodium bicarbonate, sodium carbonate, potassiumbicarbonate, potassium carbonate, potassium hydroxide, calciumhydroxide, or mixtures thereof. Preferably, the base is sodiumhydroxide.

[0038] The concentration of the base can be varied. For example, whenthe base is sodium hydroxide, the concentration of sodium hydroxide withrespect to water can be in the range of about 5 percent to about 50percent by weight sodium hydroxide to water. Preferably, the sodiumhydroxide is about 5 percent to about 20 percent by weight sodiumhydroxide to water. In a preferred embodiment of the present invention,the base is sodium hydroxide having a concentration of about 5% sodiumhydroxide with respect to water.

[0039] The number of extractions and the amount of water, base, oraqueous alcoholic solution used for each extraction can be readilydetermined by those skilled in the art. It is also noted that more thanone extraction may be performed. For example, the reaction mixture canbe extracted three times with water per extraction before extractionwith a base. Similarly, more than one basic extraction may be performed.

[0040] The term “purified 1,3,5-triisopropylbenzene” means1,3,5-triisopropylbenzene that has been purified so that the level ofany remaining impurities are less than the level of impurities found inthe impure 1,3,5-triisopropylbenzene. Preferably, the purity of the1,3,5-triisopropylbenzene is greater than 97% with respect to the1,3,5-triisopropylbenzene. More preferably, the1,3,5-triisopropylbenzene has a purity greater than 98% with respect tothe 1,3,5-triisopropylbenzene, and most preferably, the purity of the1,3,5-triisopropylbenzene is greater than 99%.

[0041] The examples presented below are intended to illustrateparticular embodiments of the invention and are not intended to limitthe scope of the specification, including the claims, in any way.

EXAMPLE 1

[0042] Neat impure 1,3,5-triisopropylbenzene (20 g) [no solvent wasadded] was placed in a round-bottom flask with 20 mol percentchlorosulfonic acid (2.28 g) with respect to 1,3,5-triisopropylbenzeneto form a reaction mixture where the acid formed a second layer on thebottom of the flask. The reaction mixture was stirred rapidly at roomtemperature (23° C.) for 30 minutes. The reaction mixture was thenquenched into 100 mL of water in a separation funnel. The bottom aqueouslayer was removed, and the reaction mixture was washed with 100 mL of 5percent sodium hydroxide to water solution. The bottom aqueous layer wasremoved, and the reaction mixture was washed with 100 mL of water toremove the salts formed during the base wash. The water layer wasremoved, and the desired purified 1,3,5-triisopropylbenzene wasobtained.

EXAMPLE 2

[0043] Neat impure 1,3,5-triisopropylbenzene (200 g) [no solvent wasadded] was placed in a round-bottom flask and stirred. Chlorosulfonicacid (22.8 g, equal to 20 mol percent with respect to the impure1,3,5-triisopropylbenzene was added over 15 minutes, with vigorousstirring. The reaction mixture was stirred an additional 15 minutes,then poured into 1000 mL water to quench the reaction.

[0044] The phases are allowed to separate, and the bottom aqueous layerwas removed. The organic layer was then washed once with 750 mL of 5%aqueous sodium hydroxide. The phases are again separated and the waterlayer discarded. The organic layer was then washed a final time with 750mL of water. The organic layer, which was purified1,3,5-triisopropylbenzene, was retained.

[0045] It is noted that in the collection procedures that use aqueoussolutions or water, the resulting purified product typically has aresidual water content of less than 0.02% KF as measured by the KarlFischer Method, which is well-known to those skilled in the art. See,for example, United States Pharmacopeia, The National Formulary, USP 23,NF 18, 1995:1840-1842, which is hereby incorporated by reference.

[0046] The following table shows the results of purification of1,3,5-triisopropylbenzene under various conditions. The procedures abovewere used with the noted variations. Amount of Sulfonating Sulfonating %1,3,5- % 1,2,4- Example Number Agent Agent Mixing Time % Ethyl IsomerTIPB TIPB Impure 0.96 91.67 4.33 1,3,5- TIPB A  3 H₂SO₄ 31 mol % 1 hr0.95 92.62 4.27 (70° C.)  4 H₃SO₄/ 50 mol %** 1 hr 1.00 92.59 4.28 FeSO₄(95° C.) 5 ClSO₃H 74 mol % 25 min Reaction Mixtute (60° C.) Solidified 6ClSO₃H 10 mol % <10 min 0.91 95.34 2.67 7 ClSO₃H 10 mol % 45 min 0.9195.00 2.82 8 ClSO₃H 20 mol % 45 min 0.62 99.27 0.04 9 ClSO₃H 15 mol % 45min 0.87 98.01 0.71 10 ClSO₃H 20 mol % <10 min 0.60 99.30 none Impure0.68 97.59 0.93 1.3,5- TIPB B 11 ClSO₃H 10 mol % <5 min 0.59 99.27 0.0512 ClSO₃H 10 mol % <5 min 0.60 99.23 0.08 13 ClSO₃H 10 mol % <5 min 0.5999.25 none (35° C.) 14 ClSO₃H 10 mol % 10 min 0.60 98.86 0.26 (4° C.) 15ClSO₃H 5 mol % <5 min 0.64 98.50 0.47 16 ClSO₃H 10 mol % <5 min 0.5999.10 0.11 17 ClSO₃H 10 mol % <5 min 0.59 99.20 0.04 (50° C.) 18 ClSO₃H20 mol % <5 min 0.42 99.46 none 19 ClSO₃H 10 mol % <5 min 0.61 99.040.10 20 ClSO₃H 10 mol % <5 min 0.60 99.14 0.05 21 ClSO₃H¹ 10 mol % 3 hrs0.58 99.30 none 22 ClSO₃H¹ 20 mol % 15 min 0.40 99.49 none 23 FSO₃H 15mol % 15 min 0.60 98.25 0.75 24 FSO₃H 20 mol % <5 min 0.60 97.81 0.81 25ClSO₃H 20 mol % <5 min 0.43 99.3 none 26 ClSO₃H 20 mol % 24 hrs nt nt nt

[0047] The base used in Examples 3-11 was 10% aqueous sodiumbicarbonate. In all other Examples except 16, 19, and 20, the base wassodium hydroxide.

[0048] In Example 16, the pure 1,3,5-triisopropylbenzene was collectedby first extracting with a 50:50 v/v mixture of methanol/water, nextextracting with sodium hydroxide, and finally extracting with a 50:50v/v mixture of methanol/water.

[0049] In Example 19, the pure 1,3,5-triisopropylbenzene was collectedby three sequential extractions of a 50:50 v/v mixture ofmethanol/water.

[0050] In Example 20, the pure 1,3,5-triisopropylbenzene was collectedby two sequential extractions with a 15% aqueous solution of ammonia,followed by extraction with water.

[0051] Purity Analysis

[0052] The purity of 1,3,5-triisopropylbenzene can be determined byvapor phase chromatography (VPC) as follows:

[0053] A DB 5 column [30 m ×0.25 mm] (J&W, Fulsom, Calif.) is used. Theinjection is 1 μL. The injector temperature was 150° C. The detectortemperature was 300° C., and the method of detection wasflame-ionization (FID). The initial temperature of the column was 115°C. for the first 15 minutes. Then the temperature was increased 10° C.per minute until 280° C., which was maintained for 10 minutes. The peakcorresponding to 1,3,5-triisopropylbenzene had a retention time (Rf) ofabout 17 minutes to about 18 minutes.

1. A method of purifying 1,3,5-triisopropylbenzene, the methodcomprising: a. combining impure 1,3,5-triisopropylbenzene with asulfonating agent to form a reaction mixture; b. mixing the reactionmixture at a temperature at about 0° C. or above; and c. collecting thepurified 1,3,5-triisopropylbenzene.
 2. The method of claim 1 wherein thesulfonating agent comprises chlorosulfonic acid.
 3. The method of claim1 wherein the sulfonating agent is about 20 mol percent of the impure1,3,5-triisopropylbenzene.
 4. The method of claim 1 wherein thesulfonating agent is in the range of about 15 mol percent to about 30mol percent of the impure 1,3,5-triisopropylbenzene.
 5. The method ofclaim 1 wherein the reaction mixture is mixed at a temperature in therange of about 0° C. to about 50° C.
 6. The method of claim 1 whereinthe reaction mixture in mixed at a temperature in the range of about 20°C. to about 30° C.
 7. The method of claim 1 wherein the reaction mixtureis mixed at room temperature.
 8. The method of claim 1 wherein thesulfonating agent comprises fluorosulfonic acid or sulfuric acid.
 9. Themethod of claim 1 wherein the reaction mixture is mixed for at least 5minutes.
 10. The method of claim 1 wherein the reaction mixture is mixedfor about 5 minutes to about 24 hours.
 11. The method of claim 1 whereinthe reaction mixture is mixed for about 5 minutes to about 60 minutes.12. The method of claim 1 wherein purified 1,3,5-triisopropylbenzene iscollected by extracting the reaction mixture first with water, secondwith a base or an aqueous alcoholic solution, and last with water. 13.The method of claim 1 wherein the purified 1,3,5-triisopropylbenzene iscollected by extracting the reaction mixture with a base or an aqueousalcoholic solution.
 14. The method of claim 12 wherein the base issodium hydroxide.
 15. The method of claim 14 wherein the sodiumhydroxide has a concentration of about five to about fifty percent byweight sodium hydroxide to water.
 16. The method of claim 14 wherein thesodium hydroxide has a concentration of about 5 percent to about 20percent by weight sodium hydroxide to water.
 17. The method of claim 14wherein the sodium hydroxide has a concentration of about 5 percent byweight sodium hydroxide to water.
 18. The method of claim 12 wherein thebase comprises sodium bicarbonate, ammonia or sodium hydroxide, ormixtures thereof.
 19. The method of claim 12 wherein the aqueousalcoholic solution is a methanol and water solution.
 20. The method ofclaim 13 wherein the aqueous alcoholic solution is a methanol and watersolution.
 21. The method of claim 18 wherein the base is 5 percent byweight sodium bicarbonate to water or 30 percent by weight ammonia towater.
 22. A method of purifying 1,3,5-triisopropylbenzene, the methodcomprising: a. combining impure 1,3,5-triisopropylbenzene with about 20mol percent chlorosulfonic acid to the 1,3,5-triisopropylbenzene to forma reaction mixture; b. mixing the reaction mixture at a temperature inthe range of about 0° C. to about 50° C. for a time in the range ofabout 10 minutes to about 24 hours; and c. collecting the purified1,3,5-triisopropylbenzene by first extracting the reaction mixture withwater, next extracting the reaction mixture with sodium hydroxide havinga concentration in the range of about 5 percent to about 50 percent byweight sodium hydroxide to water, and last extracting the reactionmixture with water.